Bacteria that are normally susceptible to attack by .beta.-lactam antibiotics can develop a resistance to such attack by the production of a .beta.-lactamase enzyme. These enzymes catalyze the hydrolysis of the lactam ring of a .beta.-lactam antibiotic to a .beta.-amino acid derivative, which is not active against bacteria.
One .beta.-lactamase enzyme is the RTEM enzyme. The RTEM enzyme is of plasmid origin and is said to be the most widely distributed .beta.-lactamase among the enteric gram-negative bacteria; see, Fisher et al., Annual Reports in Medicinal Chemistry, 13:239 (1978). The RTEM enzyme is capable of transferring into bacteria that are susceptible to .beta.-lactam antibiotics and rendering the organism resistant to these drugs; this ability to transfer from organism to organism, of course compounds the problem of the RTEM enzyme. This can be seen most clearly in the development recently of an ampicillin-resistant strain of N. gonorrhoeae.
Two approaches have been followed in the search for a way to overcome, or at least minimize, the effects of .beta.-lactamases. The first is the synthesis of novel .beta.-lactam antibiotics which are stable against .beta.-lactamases. These efforts have enjoyed some success; however, the resistant derivatives synthesized seem to have a lower degree of antibacterial activity than the non-resistant analogs. The second approach comprises the use of a compound which inhibits the action of .beta.-lactamase enzymes on the lactam ring of a .beta.-lactam antibiotic. These .beta.-lactamase inhibitors are used in conjunction with the .beta.-lactam antibiotics.